WO2022227332A1 - 一种预防和/或治疗类风湿关节炎的组合物及其制备方法与应用 - Google Patents

一种预防和/或治疗类风湿关节炎的组合物及其制备方法与应用 Download PDF

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WO2022227332A1
WO2022227332A1 PCT/CN2021/111562 CN2021111562W WO2022227332A1 WO 2022227332 A1 WO2022227332 A1 WO 2022227332A1 CN 2021111562 W CN2021111562 W CN 2021111562W WO 2022227332 A1 WO2022227332 A1 WO 2022227332A1
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parts
composition
rheumatoid arthritis
preventing
servings
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French (fr)
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黄闰月
温泽淮
黄清春
赵越
吴晓东
陈秀敏
夏璇
郭晓慧
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广东省中医院
广州中医药大学第二附属医院
广州中医药大学第二临床医学院
广东省中医药科学院
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Priority to SE2351359A priority Critical patent/SE2351359A2/en
Publication of WO2022227332A1 publication Critical patent/WO2022227332A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/17—Gnetophyta, e.g. Ephedraceae (Mormon-tea family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A61K36/714—Aconitum (monkshood)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/74—Rubiaceae (Madder family)
    • A61K36/746—Morinda
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/894—Dioscoreaceae (Yam family)
    • A61K36/8945—Dioscorea, e.g. yam, Chinese yam or water yam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention belongs to the field of traditional Chinese medicine, and in particular relates to a composition for preventing and/or treating rheumatoid arthritis and a preparation method and application thereof.
  • Rheumatoid arthritis is a common autoimmune disease, its pathological features are joint synovial inflammation and synovial tissue hyperplasia, and bone destruction is an important feature of RA joint damage, mainly including articular cartilage. and bone damage and destruction.
  • the disability problem of RA patients in my country due to bone destruction is still severe.
  • the disability rate between 5 and 10 years of illness is as high as 43.5%, and the disability rate for 30 years is 90%.
  • the bone destruction caused by the inflammation and hyperplasia of the synovium is the core pathological link of rheumatoid arthritis. Therefore, how to effectively block the bone destruction and reduce the disability rate is an urgent difficulty to be overcome in the treatment of rheumatoid arthritis.
  • DMARDs Anti-rheumatic drugs
  • MTX methotrexate
  • DMARDs are the first-line treatment for RA.
  • MTX methotrexate
  • DMARDs are greatly limited in long-term clinical application due to their side effects and poor tolerance, such as gastrointestinal symptoms, bone marrow suppression, hepatotoxicity, nephrotoxicity, infection, tumor and autonomic neuropathy, and even patients' resistance.
  • DMARDs such as biological agents have made continuous progress, due to the single-target effect, there are still problems such as rapid short-term efficacy, unstable long-term efficacy, easy relapse of patients' conditions, and incomplete safety. A heavy financial burden is imposed on the individual patient and society. At present, DMARDs, including biological agents, cannot effectively block or inhibit the pathological process of joint bone destruction in RA patients, resulting in continuous progress of imaging changes despite treatment.
  • RA belongs to the category of "arthralgia" in traditional Chinese medicine.
  • the classic prescriptions are Huangqi Guizhi Wuwu Decoction (Astragalus, Guizhi, Shaoyao, Ginger and Jujube) or Guizhi Shaoyao Zhimu Decoction (Guizhi, Shaoyao, Licorice, Ephedra , ginger, Atractylodes, Zhimu, Fangfeng and Zhifuzi) are used to treat rheumatoid arthritis, but the therapeutic effect is not very satisfactory.
  • Chinese patent application such as publication number CN 108578606 A discloses a traditional Chinese medicine preparation for the treatment of rheumatoid arthritis.
  • a composition for preventing and/or treating rheumatoid arthritis which is prepared from the following raw material components in parts by mass: 10-40 parts of Salvia miltiorrhiza, 15-120 parts of Panshanlong, 15 parts of Astragalus ⁇ 60 servings, 5-30 servings of white peony root, 3-15 servings of ephedra, 3-15 servings of cooked aconite, 5-30 servings of Morinda officinalis, and 5-30 servings of licorice root.
  • the traditional Chinese medicine composition of the present invention takes activating blood and tonifying kidney, dispelling cold and dispelling rheumatism as a treatment method, mainly for patients with cold-damp stasis syndrome, specifically:
  • Salvia miltiorrhiza activates blood and dispels blood stasis, removes stagnation of new life
  • Chuanshanlong activates blood and dreds collaterals, dispels wind and removes dampness.
  • Astragalus cooked aconite, Morinda officinalis.
  • Astragalus helps the monarch medicine to strengthen the body, strengthens the power of tonifying qi and activating blood, and it is used together with Panshanlong to strengthen the effect of righting;
  • Morinda officinalis enters the liver and kidney meridians, can nourish the liver and kidney, strengthen the muscles and bones, and can achieve twice the result with half the effort when used in combination with the monarch medicine and astragalus Efficacy; cooked aconite to dispel wind, dispel cold and relieve pain, and help monarch medicine to clear collaterals.
  • Adjuvant white peony root, ephedra. Baishao supplements astragalus, nourishes blood and softens the liver, and also controls the dryness of cooked aconite; ephedra and monarch medicine together can help to eliminate rheumatism and toxins and relieve pain.
  • the medicine Zhigancao. Licorice reconciles various medicines.
  • Salvia The dried root and rhizome of Salvia miltiorrhiza Bunge. Bitter, slightly cold. Heart, liver meridian. Removing blood stasis and relieving pain, promoting blood circulation and removing vexation.
  • Dioscorea nipponica Dioscorea nipponica Makino, a plant of the Dioscoreaceae family, is used as medicine with its rhizomes. Bitter, flat. Soothes tendons and activates collaterals, dispels wind and relieves pain.
  • Astragalus The dried root of the legume Astragalus membranaceus (Fisch.) Bge.var. mongolicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge. Gan, Wen. Return to the lung and spleen meridians. Invigorating Qi and solidifying the surface, diuretic support toxins, expelling pus, astringing sores and producing muscles.
  • Paeonia lactiflora The dried root of the Ranunculaceae plant Paeonia lactiflora Pall. Bitter, sour, slightly cold. Return to the liver and spleen meridians. Calming the liver and relieving pain, nourishing blood and regulating menstruation, astringing yin and stopping sweating.
  • Ephedra The dried herbaceous stems of Ephedra sinica Stapf, Ephedra intermedia Schrenk et C.A.Mey. or Ephedra equisetina Bge. Pungent, slightly bitter, warm. Returns to the lung and bladder meridians. Sweating and dispelling cold, dispelling lung and relieving asthma, diuresis and swelling.
  • Ripe aconite a processed product of the sub-root of the ranunculaceae Aconitum carmichaeli Debx. Pungent, sweet, hot; poisonous. Return to the heart, kidney and spleen meridians. Back to Yang to save the adversity, supplement the fire to help the Yang, and chase away the pathogens of wind, cold and dampness.
  • Morinda officinalis The dried root of Morinda officinalis How of the Rubiaceae plant. Sweet, pungent, lukewarm. Return to the kidney and liver meridians. Nourishes kidney yang, strengthens muscles and bones, and dispels rheumatism.
  • Zhigancao Leguminosae, licorice is a perennial herb. The medicinal parts are roots and rhizomes. It is made by concocting licorice with honey and boiled water. Gan, flat. The medicinal properties are mild, can sink and descend, can float and sink, and return to the heart, lung, spleen and stomach meridians. It is good at reconciling the properties of various medicines.
  • the composition for preventing and/or treating rheumatoid arthritis is made from the following raw material components in parts by mass: 30 parts of Salvia miltiorrhiza, 30 parts of Panshanlong, 30 parts of Astragalus, 10 parts of Paeonia lactiflora, and 6 parts of Ephedra , 10 parts of cooked aconite, 10 parts of Morinda officinalis, 15 parts of licorice.
  • a method for preparing the above-mentioned composition for preventing and/or treating rheumatoid arthritis the components are respectively crushed, sieved and mixed to obtain the prevention and/or treatment of rheumatoid arthritis Compositions.
  • compositions for preventing and/or treating rheumatoid arthritis in preparing a medicament for preventing and/or treating rheumatoid arthritis.
  • a traditional Chinese medicine preparation which uses the above-mentioned composition for preventing and/or treating rheumatoid arthritis as an active ingredient.
  • the traditional Chinese medicine preparation further includes medically acceptable excipients.
  • the adjuvant is at least one of a sustained release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption enhancer, an adsorption carrier, a surfactant, and a lubricant.
  • the selected adjuvants in the present invention are conventional adjuvants in the field of traditional Chinese medicine pharmacy, for example, the slow-release agent and excipient can be water, the filler can be starch, sucrose, and the binder can be cellulose derivatives, alginate, gelatin and Polyvinylpyrrolidone, wetting agent can be glycerin, disintegrating agent can be agar, calcium carbonate and sodium bicarbonate, absorption accelerator can be quaternary ammonium compound, adsorption carrier can be kaolin and bentonite, surfactant can be hexadecane Alcohol, lubricants can be talc, calcium/magnesium stearate, polyethylene glycol.
  • other adjuvants such as flavors, sweeteners, etc. can be added.
  • the dosage form of the traditional Chinese medicine preparation of the present invention can be conventional traditional Chinese medicinal forms such as decoction, tablet, capsule, pill, powder, granule, syrup and the like.
  • the composition for preventing and/or treating rheumatoid arthritis of the present invention can significantly reduce the degree of joint swelling in CIA rats, X-ray shows that bone destruction is improved, and pathological sections show that it has good inhibition of synovial tissue.
  • Proliferation, reducing inflammatory cell infiltration, and delaying the destruction of bone and cartilage significantly reduced the expression levels of inflammatory cytokines TNF- ⁇ and IL-1 ⁇ in the serum of CIA rats. It has the effects of improving symptoms, bone protection and anti-inflammatory effects on CIA rats, an animal model of rheumatoid arthritis, and has no toxicity to rats.
  • composition for preventing and/or treating rheumatoid arthritis of the present invention can improve symptoms, reduce inflammation, and at the same time have fewer adverse reactions, and has potential bone protection.
  • Figure 1 is a flow chart of the experimental design of the type II collagen (Col II)-induced arthritis (CIA) rat model
  • Fig. 2 is the body weight change trend of each group of rats in the CIA rat experimental part of the present invention
  • Fig. 3 is the thymus gland index contrast of each group of rats in the CIA rat experimental part of the present invention
  • Fig. 4 is the spleen index contrast of each group of rats in the CIA rat experimental part of the present invention.
  • Fig. 5 is the ankle joint swelling degree measurement result of each group of rats in the CIA rat experimental part of the present invention.
  • Fig. 6 is the change of ankle joint swelling degree before and after administration of each group of rats in the CIA rat experimental part of the present invention
  • Fig. 7 is the serum TNF- ⁇ result after the treatment of each group of rats in the CIA rat experimental part of the present invention.
  • Fig. 8 is the serum IL-1 ⁇ result of each group of rats in the CIA rat experimental part of the present invention after treatment;
  • Fig. 9 is a typical photograph of joint swelling after the treatment of each group of rats in the CIA rat experimental part of the present invention.
  • Fig. 10 is the X-ray photograph of the ankle joint after the treatment of each group of rats in the CIA rat experimental part of the present invention.
  • Fig. 11 is the pathological picture of ankle joint HE after the treatment of each group of rats in the CIA rat experimental part of the present invention
  • Figure 12 is an analysis diagram of the results of the ACR20 compliance rate of patients treated in clinical trials of the present invention for 4 weeks and 12 weeks;
  • Fig. 13 is the result analysis diagram of CCP titer change before and after the treatment of clinical trial patients of the present invention.
  • Fig. 14 is the result analysis diagram of rheumatoid factor RF before and after the treatment of clinical trial patients of the present invention.
  • Fig. 15 is the result analysis diagram of C-reactive protein before and after the treatment of clinical trial patients of the present invention.
  • Fig. 16 is the result analysis diagram of erythrocyte sedimentation rate before and after the treatment of clinical trial patients of the present invention.
  • Figure 17 is an analysis diagram of bone erosion score before and after treatment of clinical trial patients of the present invention.
  • Figure 18 is an analysis diagram of the bone edema score before and after the treatment of clinical trial patients of the present invention.
  • Figure 19 is an analysis diagram of typical nuclear magnetic resonance images before and after treatment of clinical trial patients of the present invention.
  • Figure 20 is an analysis diagram of serum alanine aminotransferase results before and after the treatment of clinical trial patients of the present invention.
  • Figure 21 is an analysis diagram of aspartate aminotransferase results before and after treatment of clinical trial patients of the present invention.
  • Figure 22 is an analysis diagram of the results of serum creatinine before and after treatment in the clinical trial patients of the present invention.
  • the traditional Chinese medicine decoction for preventing and/or treating rheumatoid arthritis is prepared from the following components: 30 g of Salvia miltiorrhiza, 30 g of Panshanlong, 30 g of Astragalus, 10 g of Paeonia lactiflora, 6 g of Ephedra, 10 g of cooked aconite, 10 g of Morinda officinalis, and 15 g of Zhigancao.
  • bovine type II collagen (Lot: 20021, Chondrex, USA) and incomplete Freund The adjuvant (Lot: 7002, Chondrex, USA) was mixed and emulsified at a volume ratio of 1:1, and was emulsified with a homogenizer (IKA Germany) was homogenized for 30 min.
  • a homogenizer IKA Germany
  • composition group was given the traditional Chinese medicine decoction of Example 1, and the daily dosage was converted into a clinical equivalent dose of 10.8 g/kg, which was administered by gavage once a day; the methotrexate group was given methotrexate (MTX) intervention,
  • the dose converted into a clinical equivalent dose was 1.02 mg/kg/week, which was administered by intraperitoneal injection; the rats in the normal group and the CIA model group were given normal saline by gavage every day; the administration period in all groups was 35 days.
  • the drug interventions in each group are shown in Table 1:
  • the composition group was compared with the normal group, the CIA model group and the MTX group, and the swelling degree of the hind foot and ankle joints of the rats, the X-ray imaging changes of the hind limbs of the rats, the joint pathological sections, and the serum inflammatory cytokines and tumor necrosis were observed.
  • the serum IL-1 ⁇ levels of the rats in each group after treatment are shown in Figure 8. It can be seen from Figure 8 that compared with the normal group, the serum IL-1 ⁇ levels in the CIA model group were significantly increased (p ⁇ 0.05). The expression of serum IL-1 ⁇ in both the composition group and the methotrexate group was significantly decreased (p ⁇ 0.05). It can be seen that the traditional Chinese medicine composition of the present invention has a significant down-regulation effect on the serum interleukin-1 ⁇ level of CIA rats, and has a significant anti-inflammatory effect.
  • Figure 9 shows typical photos of joint swelling of rats in each group after treatment. It can be seen from Figure 9 that after 1 month of treatment and administration, the degree of foot swelling of CIA rats in the composition group is less than that in the model group.
  • Figure 10 shows the X-ray photographs of the hind ankle joints of the rats in each group after treatment.
  • the part circled by the small red circle in the figure shows the local worm-eaten changes of the hind ankle joint
  • the part circled by the large yellow circle shows The soft tissue of the hind foot and ankle joint was swollen. It can be seen from Figure 10 that after 1 month of treatment and administration, the swelling of the footpad and the degree of joint damage of the CIA rats in the composition group were less than those in the model group. This shows that the traditional Chinese medicine composition of the present invention can improve the swelling of the foot pad, joint destruction and the like in CIA rats.
  • composition for preventing and/or treating rheumatoid arthritis of the present invention can significantly reduce the degree of joint swelling in CIA rats, X-ray shows that bone destruction is improved, and pathological section shows that it can effectively inhibit the proliferation of synovial tissue and reduce the infiltration of inflammatory cells. , delaying the destruction of bone and cartilage, and significantly reducing the expression levels of inflammatory cytokines TNF- ⁇ and IL-1 ⁇ in serum of CIA rats. It can improve symptoms, protect bone and anti-inflammatory effects on CIA rats, an animal model of rheumatoid arthritis, and has no toxicity to rats.
  • composition for preventing and/or treating rheumatoid arthritis of the present invention was administered to 11 RA patients with low disease activity, and the therapeutic effect was evaluated after 3 months of treatment.
  • the research subjects should meet the following diagnostic criteria: 1 Western medicine diagnostic criteria: comprehensive judgment based on the RA classification criteria of the 2010 ACR/EULAR; 2 RA patients with RA imaging progression of grades I, II, and III (refer to Diagnostic criteria revised by the American Academy of Rheumatology (ARA) in 1987);
  • DMARDs disease-modifying antirheumatic drugs
  • the level of aspartate aminotransferase or alanine aminotransferase is 1.5 times higher than the upper limit of the normal range;
  • Example 1 of the present invention The traditional Chinese medicine decoction of Example 1 of the present invention, one dose per day, 150 mL per dose, divided into 2 warm doses, twice a day.
  • Figure 12 is an analysis of the results of the ACR20 compliance rate of patients treated for 4 weeks and 12 weeks. According to international RA-related clinical research reports, the 12-week ACR20 compliance rate of methotrexate alone in the treatment of rheumatoid arthritis was 39.3% (see Weinblatt, ME for details). ,Mease,P,Mysler,E,et al.The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate:results from a multinational,phase IIb,randomized,double-blind, placebo/active-controlled, dose-ranging study.
  • composition of the present invention alone has a similar curative effect to MTX in treating RA with low disease activity for 3 months, and has potential The role of bone protection.
  • Figure 13 is an analysis diagram of the results of changes in CCP titer before and after treatment. It can be seen from the figure that there is no difference in the CCP titer before and after treatment (P>0.05). On the whole, the CCP antibody titer of patients after treatment has improved, and the proportion of low titers has decreased. prompt improvement. Some studies have pointed out that the titer of CCP is related to the osteoporosis of patients, so after treatment, the decrease of CCP titer can indicate that osteoporosis and osteopenia will also improve.
  • Fig. 14 is the result analysis chart of rheumatoid factor RF before and after treatment.
  • rheumatoid factor serum levels before and after treatment.
  • P>0.05 the expression of rheumatoid factor serum levels before and after treatment.
  • the RF levels of patients before and after treatment decreased, indicating that the condition improved.
  • Figures 15 and 16 are results analysis diagrams of C-reactive protein and erythrocyte sedimentation rate (inflammation index) before and after treatment. It can be seen from the figure that there was no statistical difference in C-reactive protein and erythrocyte sedimentation rate before and after treatment (P>0.05), but from the overall level, both of them were decreased to varying degrees, indicating that inflammation has been controlled to a certain extent, while inflammation It is a direct influencing factor of bone destruction, so it can be speculated that after treatment, the levels of C-reactive protein and erythrocyte sedimentation rate decreased, which delayed the process of bone destruction.
  • Figures 17, 18, and 19 are analysis diagrams of bone erosion, bone edema scores, and typical MRI images before and after treatment. It can be seen from the figure that there was no significant difference in bone erosion and bone edema scores before and after treatment (P>0.05).
  • the inventive compositions for preventing and/or treating rheumatoid arthritis have potential bone-protective potential.
  • Figures 20, 21, and 22 are the analysis diagrams of the results of serum alanine aminotransferase, aspartate aminotransferase, and serum creatinine before and after treatment. As can be seen from the figure, there is no significant statistical difference in the level expression of alanine aminotransferase, aspartate aminotransferase, and serum creatinine before and after treatment, indicating that the composition for preventing and/or treating rheumatoid arthritis of the present invention has no obvious effect on liver and kidney function. influences.
  • composition for preventing and/or treating rheumatoid arthritis of the present invention can improve symptoms, reduce inflammation, and at the same time have less adverse reactions, and has potential bone protection effect.

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Abstract

一种预防和/或治疗类风湿关节炎的组合物及其制备方法与应用。该组合物以质量份计由如下原料组分制成：丹参10-40份、穿山龙15-120份、黄芪15-60份、白芍5-30份、麻黄3-15份、熟附子3-15份、巴戟天5-30份、炙甘草5-30份。经临床试验证明，该组合物可改善患者关节肿痛症状，控制炎症水平与病情进展，且具有潜在的骨保护作用。

Description

一种预防和/或治疗类风湿关节炎的组合物及其制备方法与应用 技术领域
本发明属于中药领域，具体涉及一种预防和/或治疗类风湿关节炎的组合物及其制备方法与应用。
背景技术
类风湿关节炎(Rheumatoid arthritis，RA)是一种常见的自身免疫性疾病，其病理特征表现为关节滑膜炎症及滑膜组织增生，而骨破坏是RA关节损坏的重要特征，主要包括关节软骨和骨的损伤与破坏。我国的RA患者因骨破坏引发致残问题依然严峻，患病5-10年之间的致残率高达43.5％，病程30年的致残率为90％。关节滑膜的炎症增生导致的骨破坏是类风湿关节炎的核心病理环节，所以如何有效阻断骨破坏、降低致残率，是类风湿关节炎治疗中亟待克服的难点。
西医治疗方案虽然可以在短期内较为有效地控制病情，但是仍无法完全有效地长期稳定病情，尤其是无法有效阻止影像学进展(即阻止骨破坏进程)。抗风湿药物(DMARD)如甲氨蝶呤(MTX)是RA的一线治疗药物，早期、足量、联合使用DMARD药物是改善RA预后的关键，但是40％的患者对早期诱导缓解方案不应答，且DMARD因其胃肠道症状、骨髓抑制、肝毒性、肾毒性、感染、肿瘤及自主神经病变等副作用及耐受性差而在临床的长期应用中受到极大的限制，乃至患者的抵触。虽然新型DMARD如生物制剂不断取得进展，但是由于单靶点作用，仍然存在短期疗效迅速、长期疗效不稳定、患者病情易反复、安全性不完全明确的问题，并且国内生物制剂昂贵的治疗价格给患者个人和社会带来了沉重的经济负担。目前，包括生物制剂在内的DMARD也无法有效阻断或抑制RA患者的关节骨质破坏病理进程，导致影像学改变在治疗情况下仍持续进展。
RA在中医上属于“痹证”的范畴，经典药方如黄芪桂枝五物汤(黄芪、桂枝、芍药、生姜及大枣)或桂枝芍药知母汤(桂枝、芍药、甘草、麻黄、生姜、白术、知母、防风及炙附子)被用于治疗类风湿关节炎，但治疗效果并不十分理想。此外，如公开号为CN 108578606 A的中国专利申请公开了一种治疗类风湿关节炎的中药制剂，由黄芪35、桂枝15、炒白芍25、炙附子10、当归15、薏苡仁25、防风15、秦艽15、羌活10、川芎10、苍术15、甘草15组成，对类风湿具有一定治疗作用，但能否阻断或抑制RA患者的关节骨质破坏病理进程仍需进一步探究。
发明内容
根据本发明的一个方面，提供了一种预防和/或治疗类风湿关节炎的组合物，以质量份计由如下原料组分制成：丹参10～40份、穿山龙15～120份、黄芪15～60份、白芍5～30份、麻黄3～15份、熟附子3～15份、巴戟天5～30份、炙甘草5～30份。
本发明的中药组合物以活血补肾，散寒祛风湿为治法，主要针对寒湿瘀阻证病人，具体地：
君药：丹参、穿山龙。丹参活血祛瘀，去滞生新；穿山龙活血通络，祛风除湿。
臣药：黄芪、熟附子、巴戟天。黄芪助君药以扶正，加强补气活血之力，与穿山龙同用则强化扶正之效；巴戟天入肝肾经，可补肝肾、强筋骨，与君药和黄芪合用可达事半功倍之效；熟附子祛风散寒止痛，助君药以通络。
佐药：白芍、麻黄。白芍佐黄芪、养血柔肝，兼制熟附子之燥；麻黄与君药同用，可助祛除风湿毒邪、止痛。
使药：炙甘草。甘草调和诸药。
方中：
丹参：唇形科植物丹参Salvia miltiorrhiza Bunge.的干燥根及根茎。苦，微寒。归心、肝经。祛瘀止痛，活血通经，清心除烦。
穿山龙：薯蓣科薯蓣属植物穿龙薯蓣Dioscorea nipponica Makino，以根状茎入药。苦，平。舒筋活络，祛风止痛。
黄芪：豆科植物蒙古黄芪Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao或膜荚黄芪Astragalus membranaceus(Fisch.)Bge.的干燥根。甘，温。归肺、脾经。补气固表，利尿托毒，排脓，敛疮生肌。
白芍：毛茛科植物芍药Paeonia lactiflora Pall.的干燥根。苦、酸，微寒。归肝、脾经。平肝止痛，养血调经，敛阴止汗。
麻黄：麻黄科植物草麻黄Ephedra sinica Stapf、中麻黄Ephedra intermedia Schrenk et C.A.Mey.或木贼麻黄Ephedra equisetina Bge.的干燥草质茎。辛、微苦，温。归肺、膀胱经。发汗散寒，宣肺平喘，利水消肿。
熟附子：毛茛科植物乌头Aconitum carmichaeli Debx.的子根的加工品。辛、甘，大热；有毒。归心、肾、脾经。回阳救逆，补火助阳，逐风寒湿邪。
巴戟天：茜草科植物巴戟天Morinda officinalis How的干燥根。甘，辛，微温。归肾、肝经。补肾阳，强筋骨，祛风湿。
炙甘草：豆科、甘草属多年生草本，药用部位是根及根茎，为将甘草用蜂蜜、开水炮制而成。甘，平。药性缓和，能沉能降，能浮能沉，归心、肺、脾、胃经。既能补中益气，又善于调和诸药性能。
在一些实施方式中，预防和/或治疗类风湿关节炎的组合物以质量份计由如 下原料组分制成：丹参30份、穿山龙30份、黄芪30份、白芍10份、麻黄6份、熟附子10份、巴戟天10份、炙甘草15份。
根据本发明的另一个方面，提供了上述的预防和/或治疗类风湿关节炎的组合物的制备方法：将各组分分别粉碎、过筛、混合，得到预防和/或治疗类风湿关节炎的组合物。
根据本发明的另一个方面，提供了上述的预防和/或治疗类风湿关节炎的组合物在制备预防和/或治疗类风湿关节炎药物中的应用。
根据本发明的另一个方面，提供了一种中药制剂，其以上述的预防和/或治疗类风湿关节炎的组合物为有效成分。
在一些实施方式中，中药制剂还包括医学上可接受的辅料。优选的，辅料为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、吸附载体、表面活性剂、润滑剂中的至少一种。本发明所选辅料为中药制药领域的常规辅料，例如，缓释剂、赋形剂可为水，填充剂可为淀粉、蔗糖，粘合剂可为纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮，湿润剂可为甘油，崩解剂可为琼脂、碳酸钙和碳酸氢钠，吸收促进剂可为季铵化合物，吸附载体可为高岭土和皂粘土，表面活性剂可为十六烷醇，润滑剂可为滑石粉、硬脂酸钙/镁、聚乙二醇。此外还可加入其它辅剂如香味剂、甜味剂等。
本发明的中药制剂的剂型可为汤剂、片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂等常规中药剂型。
根据本发明的另一个方面，提供了一种上述的中药制剂在制备预防和/或治疗类风湿关节炎药物中的应用。
经CIA大鼠模型实验证明，本发明的预防和/或治疗类风湿关节炎的组合物可明显减轻CIA大鼠关节肿胀度，X线显示改善骨破坏，病理切片显示有良好的抑制滑膜组织增殖、减少炎症细胞浸润、延缓骨与软骨破坏的效果，显著降低CIA大鼠血清中炎症细胞因子TNF-α和IL-1β表达水平。对类风湿关节炎动物模型CIA大鼠具有改善症状、骨保护及抗炎的作用，且对大鼠无毒性。
经临床试验证明，本发明的预防和/或治疗类风湿关节炎的组合物可改善症状、减轻炎症，同时不良反应少，且具有潜在的骨保护作用。
附图说明
图1是二型胶原(ColⅡ)诱导关节炎(CIA)大鼠模型实验设计流程图；
图2是本发明CIA大鼠实验部分各组大鼠的体重变化趋势；
图3是本发明CIA大鼠实验部分各组大鼠的胸腺指数对比；
图4是本发明CIA大鼠实验部分各组大鼠的脾脏指数对比；
图5是本发明CIA大鼠实验部分各组大鼠的踝关节肿胀度测量结果；
图6是本发明CIA大鼠实验部分各组大鼠给药前后踝关节肿胀度变化；
图7是本发明CIA大鼠实验部分各组大鼠治疗后的血清TNF-α结果；
图8是本发明CIA大鼠实验部分各组大鼠治疗后的血清IL-1β结果；
图9是本发明CIA大鼠实验部分各组大鼠治疗后的关节肿胀典型照片；
图10是本发明CIA大鼠实验部分各组大鼠治疗后的踝关节X光拍照图；
图11是本发明CIA大鼠实验部分各组大鼠治疗后的踝关节HE病理图；
图12是本发明临床试验患者治疗4周和12周ACR20达标率结果分析图；
图13是本发明临床试验患者治疗前后CCP滴度变化的结果分析图；
图14是本发明临床试验患者治疗前后类风湿因子RF的结果分析图；
图15是本发明临床试验患者治疗前后C-反应蛋白的结果分析图；
图16是本发明临床试验患者治疗前后血沉的结果分析图；
图17是本发明临床试验患者治疗前后骨侵蚀评分分析图；
图18是本发明临床试验患者治疗前后骨水肿评分分析图；
图19是本发明临床试验患者治疗前后典型核磁共振图片分析图；
图20是本发明临床试验患者治疗前后血清谷丙转氨酶结果分析图；
图21是本发明临床试验患者治疗前后谷草转氨酶结果分析图；
图22是本发明临床试验患者治疗前后血清肌酐结果分析图。
具体实施方式
下面结合具体实施例对本发明作进一步详细的说明。
实施例1
预防和/或治疗类风湿关节炎的中药汤剂，由以下组分制备得到：丹参30g、穿山龙30g、黄芪30g、白芍10g、麻黄6g、熟附子10g、巴戟天10g、炙甘草15g。
本实施例的中药汤剂采取下述方法制备得到：
将原料按重量配比称取后分别粉碎、过筛、混合，得到预防和/或治疗类风湿关节炎的组合物，向得到的预防和/或治疗类风湿关节炎的组合物中加入3000mL离子水煎煮60min，去渣离心，水提液经过旋转蒸发剩余得到150mL溶液，即得。
上述中药汤剂作为预防和/或治疗类风湿关节炎药物时，给予患者每日一剂，每剂150mL，分2次口服，一日两次。
应该说明的是，上述中药汤剂的制备方式只是示例性的，并不对本发明所保护的范围做限制，当然，还可以采用本领域通常使用技术进行制备，在此不一一举出。
下面，为探究本发明的预防和/或治疗类风湿关节炎的组合物对类风湿关节炎的治疗效果，进行二型胶原(ColⅡ)诱导关节炎(CIA)大鼠模型实验和临床试验。
一、二型胶原(ColⅡ)诱导关节炎(CIA)大鼠模型实验
1、实验对象
40只8周龄雌性SPF级健康Wistar大鼠，体重180～220g，随机分为4组：正常组、CIA模型组、甲氨蝶呤组(简称MTX组)、组合物组，每组10只。
2、造模方法及给药
除正常组外，其余各组均用牛二型胶原蛋白诱导构建类风湿关节炎大鼠模型，具体造模方法为：牛二型胶原蛋白(Lot:20021,Chondrex,USA)与不完全弗氏佐剂(Lot:7002,Chondrex,USA)按照体积比1:1混合乳化，用匀浆机(IKA
Figure PCTCN2021111562-appb-000001
Germany)匀浆30min，在第一天用体积分数为10％的水合氯醛将大鼠麻醉后，在大鼠尾部皮下、爪部皮下多点注射200ug/只；第八天加强免疫一次(100ug/只)，造模共计14天，得到II型胶原诱导型关节炎(CIA)大鼠模型，在此CIA模型基础上，第15天开始连续给药35天。实验设计流程如图1所示。
组合物组给予实施例1的中药汤剂，每天的给药剂量换算成临床等效剂量为10.8g/kg，每天灌胃1次；甲氨蝶呤组给予甲氨蝶呤(MTX)干预，给药剂量换算成临床等效剂量为1.02mg/kg/周，通过腹腔注射给药；正常组和CIA模型组大鼠每天给予生理盐水灌胃；所有组给药周期均为35天。各组药物干预情况(均换算成临床给药剂量)如表1所示：
表1各组药物干预情况
组别 动物数目/只 造模 给药
正常组 10 无 生理盐水
CIA模型组 10 CIA模型 生理盐水
MTX组 10 CIA模型 MTX(1.02mg/kg/周2次)
组合物组 10 CIA模型 实施例1的中药汤剂(10.8g/kg/d)
实验第50天，将组合物组同正常组、CIA模型组、MTX组比较，观察大鼠后足踝关节肿胀度、大鼠后肢X线影像学改变、关节病理切片、血清炎症细胞因子肿瘤坏死因子α(TNF-α)和白介素1β(IL-1β)表达水平以及体重、脾脏胸腺系数表达情况。
3、实验结果
(1)体重、胸腺系数、脾脏系数
各组大鼠的体重变化趋势如图2所示，胸腺系数对比如图3所示，脾脏系数对比如图4所示。从图2-4可以看出，各组大鼠体重、胸腺系数、脾脏系数均无统计学差异(p＞0.05)。由此表明，本发明的中药组合物对CIA大鼠体重、 胸腺系数、脾脏系数无明显影响。
(2)踝关节肿胀度
各组大鼠的踝关节肿胀度测量结果如图5所示，给药前后踝关节肿胀度变化如图6所示。从图5可以看出，治疗一周后模型组大鼠关节肿胀度相对其他三组大鼠明显增大。从图6可以看出，治疗1个月后，组合物组和甲氨蝶呤组相对于模型组关节肿胀度明显下降(p＜0.05)。由此表明，本发明的中药组合物可明显改善CIA大鼠关节肿胀程度。
(3)血清炎症指标
各组大鼠治疗后的血清TNF-α结果如图7所示，从图7可以看出，相对于正常组，CIA模型组血清TNF-α水平显著升高(p＜0.05)，用药治疗后，组合物组与甲氨蝶呤组大鼠血清TNF-α表达均显著减少(p＜0.05)，而且组合物组下降更加明显(P＜0.01)。由此可见本发明的中药组合物对CIA大鼠血清肿瘤坏死因子α水平有明显下调作用，抗炎作用显著。
各组大鼠治疗后的血清白介素1β水平如图8所示，从图8可以看出，相对于正常组，CIA模型组血清IL-1β水平显著升高(p＜0.05)，用药治疗后，组合物组与甲氨蝶呤组大鼠血清IL-1β表达均显著减少(p＜0.05)。由此可见本发明的中药组合物对CIA大鼠血清白介素1β水平有明显下调作用，抗炎作用显著。
(4)大鼠足垫肿胀、炎性细胞浸润和关节破坏等情况
各组大鼠治疗后的关节肿胀典型照片如图9所示，从图9可以看出，经1个月治疗给药后，组合物组CIA大鼠足肿胀程度较模型组减轻。
各组大鼠治疗后的后足踝关节的X光拍照图如图10所示，图中红色小圆圈圈起来的部分显示后足踝关节局部虫蚀样改变，黄色大圆圈圈起来的部分显示后足踝关节软组织肿胀，从图10可以看出，经1个月治疗给药后，组合物组CIA大鼠足垫肿胀、关节破坏程度较模型组减轻。由此表明，本发明的中药组合物可改善CIA大鼠足垫肿胀、关节破坏等情况。
各组大鼠治疗后的膝关节、后足踝关节的组织病理结果分析如图11所示，从图11可以看出，模型组关节面消失且关节腔多炎性细胞浸润，滑膜增生，结缔组织炎性细胞浸润严重，组合物组关节腔较为干净，炎症浸润、滑膜增生等情况明显改善。由此表明，本发明的中药组合物可改善CIA大鼠踝关节滑膜组织增殖、减少炎症细胞浸润、延缓骨与软骨破坏。
结论：本发明的预防和/或治疗类风湿关节炎的组合物可明显减轻CIA大鼠关节肿胀度，X线显示改善骨破坏，病理切片显示有良好的抑制滑膜组织增殖、减少炎症细胞浸润、延缓骨与软骨破坏的效果，显著降低CIA大鼠血清中炎症细胞因子TNF-α和IL-1β表达水平。对类风湿关节炎动物模型CIA大鼠具有改善症状、骨保护及抗炎的作用，且对大鼠无毒性。
二、临床试验
对11例低疾病活动度RA患者给予本发明的预防和/或治疗类风湿关节炎的组合物，进行3个月的治疗后进行疗效评价。
1、纳入标准
(1)研究受试对象应符合以下诊断标准：①西医诊断标准：采用2010年ACR/EULAR的RA分类标准进行综合判断；②且RA影像学进展为Ⅰ、Ⅱ、Ⅲ级的RA患者(参照1987年美国风湿病学会(ARA)修订的诊断标准)；
(2)按DAS28-CRP评分，疾病处于低活动期的患者(DAS28-CRP<3.2)；
(3)年龄在18～65岁；
(4)未曾接受病情缓解性抗风湿药(DMARDs)治疗，如MTX或LEF等，如曾接受DMARDs的治疗，需停用至少1个月；
(5)由受试者或其家属(监护人)签署的同意参加本试验的书面知情同意书。
2、排除标准
(1)合并其他自身免疫性疾病史，如干燥综合征、系统性红斑狼疮等；患有急性或慢性感染性疾病，包括乙型肝炎或丙型肝炎感染；既往具有癌症病史；活动性、潜伏性或治疗不当的结核分枝杆菌感染的证据；
(2)合并严重的心血管、脑、肺、肝、肾、造血疾病的患者；
(3)孕妇、哺乳期妇女或者有已知精神障碍的患者；
(4)血红蛋白水平不到90g/L，白细胞计数小于3.0×10^9/L，或血小板计数低于100×10^9/L的患者；
(5)肾小球滤过率低于40ml/min的患者；
(6)天冬氨酸氨基转移酶或丙氨酸氨基转移酶水平高于正常范围上限1.5倍；
(7)长期使用非甾体抗炎药导致的活动性胃十二指肠溃疡或胃炎患者；
(8)对试验药物过敏的患者；
(9)筛查4周内参与其他临床试验的患者。
3、用药措施
本发明实施例1的中药汤剂，每日一剂，每剂150mL，分2次温服，一日两次。
4、疗程与随访
(1)疗程：3个月；
(2)随访时间：筛选入组0天、4周±3天、12周±5天。
5、治疗结果
图12是治疗4周和12周病人ACR20达标率结果分析图，根据国际RA相关临床研究报道，甲氨蝶呤单用治疗类风湿关节炎12周ACR20达标率为39.3％(详见Weinblatt,ME,Mease,P,Mysler,E,et al.The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate:results from a multinational,phase IIb,randomized,double-blind,placebo/active-controlled,dose-ranging study.Arthritis Rheumatol 2015；67:2591-2600.)，结果提示本发明的组合物单用治疗低疾病活动度RA 3个月与MTX的疗效相仿，且具有潜在骨保护的作用。
图13是治疗前后对CCP滴度变化的结果分析图。从图中可以看出，治疗前后CCP滴度情况无差异性(P>0.05)，从整体上看，治疗后患者的CCP抗体滴度有所改善，低滴度所占比例均有所下降，提示病情好转。有研究指出，CCP的滴度高低与患者骨质疏松情况相关，故患者经治疗后，CCP滴度降低可提示，骨质疏松、骨量减少情况也随之好转。
图14是治疗前后对类风湿因子RF的结果分析图。从图中可以看出，治疗前后类风湿因子血清水平表达无差异性(P>0.05)，从整体上看，治疗前后患者的RF水平有所下降，提示病情好转。有研究表明，RF血清水平高低与类风湿关节炎骨破坏密切相关，故由经治疗后RF水平下降可推测，骨破坏的情况也会较前改善。
图15、16是治疗前后对C-反应蛋白、血沉(炎症指标)的结果分析图。从图中可以看出，治疗前后C-反应蛋白、血沉均无统计学差异(P>0.05)，但从总体水平来看，二者均有不同程度下降，提示炎症得到一定的控制，而炎症是骨破坏的直接影响因素，故可推测经治疗后，C-反应蛋白、血沉水平下降，延缓了骨破坏的进程。
图17、18、19是治疗前后骨侵蚀、骨水肿评分、典型核磁共振图片分析图。从图中可以看出，治疗前后骨侵蚀、骨水肿评分均无统计学差异(P>0.05)，但从患者的核磁共振结果分析，治疗前后患者骨侵蚀及骨水肿均有所改善，提示本发明的预防和/或治疗类风湿关节炎的组合物有潜在骨保护潜能。
图20、21、22是治疗前后血清谷丙转氨酶、谷草转氨酶、血清肌酐结果分析图。从图中可以看出，谷丙转氨酶、谷草转氨酶、血清肌酐在治疗前后水平表达均无明显统计学差异，说明本发明的预防和/或治疗类风湿关节炎的组合物对肝肾功能无明显影响。
综上所述，本发明的预防和/或治疗类风湿关节炎的组合物可改善症状、减轻炎症，同时不良反应少，且具有潜在的骨保护作用。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、 替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (8)

  1. 预防和/或治疗类风湿关节炎的组合物，其特征在于，以质量份计由如下原料组分制成：丹参10～40份、穿山龙15～120份、黄芪15～60份、白芍5～30份、麻黄3～15份、熟附子3～15份、巴戟天5～30份、炙甘草5～30份。
  2. 根据权利要求1所述的预防和/或治疗类风湿关节炎的组合物，其特征在于，以质量份计由如下原料组分制成：丹参30份、穿山龙30份、黄芪30份、白芍10份、麻黄6份、熟附子10份、巴戟天10份、炙甘草15份。
  3. 一种如权利要求1或2所述的预防和/或治疗类风湿关节炎的组合物的制备方法，其特征在于，将各组分分别粉碎、过筛、混合，得到预防和/或治疗类风湿关节炎的组合物。
  4. 一种如权利要求1或2所述的预防和/或治疗类风湿关节炎的组合物在制备预防和/或治疗类风湿关节炎药物中的应用。
  5. 一种中药制剂，其特征在于，其以权利要求1或2所述的预防和/或治疗类风湿关节炎的组合物为有效成分。
  6. 根据权利要求5所述的中药制剂，其特征在于，还包括医学上可接受的辅料。
  7. 根据权利要求6所述的中药制剂，其特征在于，所述辅料为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、吸附载体、表面活性剂、润滑剂中的至少一种。
  8. 权利要求5-7任一项所述的中药制剂在制备预防和/或治疗类风湿关节炎药物中的应用。
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